The global HIV/AIDS epidemic continues to expand, driven chiefly by sexual transmission of the virus and sharing of contaminated needles among intravenous drug users. The Global Fund and PEPFAR, the two international programs providing the lion's share of antiviral drugs in the developing world, are unable to keep pace with the epidemic. For every 10 subjects placed on antiviral therapy, 16 individuals are newly infected. As the number of infections increases and funds for lifelong treatment become more limited, a serious gap in HIV/AIDS care will inevitably emerge. What can be done to close this gap? Strikingly, the pathogenic challenge posed by lentiviruses, such as HIV-1, has been successfully met in 40+ species of monkeys who have coevolved with their lentiviruses. Surprisingly, the solution is not to suppress the virus, but rather to modify the host response to the virus in a manner that prevents disease. These animals essentially ignore their lentivirus, by failing to mount chronic inflammatory and immune activation responses, such as those found in HIV- infected humans. We recently found that the vast majority of CD4 T cells dying in HIV-infected lymphoid tissues are victims of an intensely inflammatory form of programmed cell death termed pyroptosis, which involves caspase-1 activation and inflammasome assembly. Remarkably, this pathway appears to be selectively activated in pathogenic but not non-pathogenic lentiviral infections. We now propose to determine if small-molecule inhibitors of the caspase 1/inflammasome/pyroptosis pathway can block clinical progression to AIDS. Caspase-1 inhibitors are already in clinical trials. If successful, this host-focused strategy could be use as a novel and cost-effective means to prevent disease progression, potentially transforming the care of millions of HIV-infected subjects who are unable to access antiviral therapy. This approach could help realize the dream of an AIDS-free generation. P